Cognitive impairment occurs in a large percent of lupus patients. We have recently demonstrated that a subset of anti-DNA antibodies in patients with SLE binds to a defined linear epitope on the NR2 NMDA receptor. These antibodies can be found in the cerebrospinal fluid (CSF) as well as in serum. We propose now to explore further the antigenicity of the NR2 receptor in SLE and the functional consequences of anti-receptor antibodies. We will study serum from lupus patients to determine whether there are antibodies to other epitopes that function as a receptor agonists or antagonists and whether there is T cell recognition of NR2 epitopes. We will also study rodent models to deter-mine whether serum antibody can penetrate an intact blood-brain-barrier, what concentrations of antibody that must be present in the CSF to cause disease, and whether there are selectively vulnerable populations of neurons. Finally, we will perform magnetic resonance imaging and spectroscopy to correlate in vivo imaging abnormalities with histopathology. This study will be performed in conjunction with a study determining if there is an association of anti-NR2 antibody, MR imaging and spectroscopy, and cognitive function in a cohort of lupus patients (P.I.: Michael Lockshin). The overall goal of this collaborative interactive program is to develop the scientific foundation for preventative therapies for cognitive decline in SLE.